When muscles (muscular substances and muscular tissues) of healthy mammals including human are applied with an excessive burden, part of such muscles are worn out. Yet, such muscles normally have a capacity for regeneration and part of the above-mentioned worn muscles promptly regenerates and enlarges for bearing the above-mentioned burden.
The regeneration and enlargement of the above-mentioned muscle normally take place as follows: that is, when the above-mentioned muscle is given stimulation such as the above-mentioned burden, satellite cells, which are located between the basal membrane of cells of the muscular fiber of such a muscle (myocytes) and sarcolemma membrane are activated to begin proliferation. Here, the above-mentioned satellite cell corresponds to a stem cell that possesses ability to differentiate to multiple lineages of cells (pluripotency) and ability to maintain their pluripotency even after undergoing cell division (self-renewing ability). And, the above-mentioned proliferated satellite cells become myoblast cells, from which cells of the muscular fiber originate, and the resulting myoblast cells fuse with existing muscular fibers; and muscles containing such fused muscular fibers will regenerate and enlarge.
On the other hand, in a patient with the muscular disorder who for some reason has damage (disease) in the muscle, an ability of the above-mentioned muscle to regenerate is extremely decreased, or the above-mentioned muscular fiber is easily degraded (worn out) even if the ability of such a muscle to regenerate is maintained. Due to this, the rate of degradation of the above-mentioned muscle exceeds the rate of regeneration thereof in the above-mentioned patient with the muscular disorder, which often brings about muscular atrophy.
In addition, in a patient with muscular dystrophy among the above-mentioned muscular disorders, which is a typical myopathy, the rate of degradation of the above-mentioned muscular fiber is higher than the rate of regeneration thereof in relative to a healthy subject even though the degradation and regeneration of the above-mentioned muscular fiber repeatedly take place. Due to this, the above-mentioned patient with the myopathy will have a gradually progressing atrophy of his/her own muscles, which results in death early in life.
As a method of treating the muscular disorder or myopathy stated above, a number of methods of enhancing (improving) the rate of regeneration of the above-mentioned muscle have been reported (Non-patent Documents 1 to 3). Yet, as it stands at this point in time, a good method of treatment has not been established.
Meanwhile, in nerve regenerative medicine, examples of methods of regenerating (elongating) damaged axons include a method of degrading chondroitin sulfate (CS) present outside cells in the nervous system.
The above-mentioned chondroitin sulfate (CS) is a major extracellular matrix component in the nervous system and is a component involved in formation of the neural network. Meanwhile, the above-mentioned chondroitin sulfate (CS) serves as a component that inhibits the regeneration of the above-mentioned axon in the cranial nerve system of an adult who has had a traumatic injury such as a spinal cord injury. That is, the above-mentioned chondroitin sulfate (CS) serves both as a necessary component and an inhibitory component in accordance with the situation.
In view of this, when a chondroitinase of bacterial origin including for example chondroitinase ABC (ChABC) is administered to an area of nerve damage affected by the above-mentioned traumatic injury, wherein the chondroitinase degrades chondroitin sulfate (CS) that is expressed in such an area, such a chondroitinase ABC exerts its action on the above-mentioned chondroitin sulfate (CS) to degrade (remove) such a chondroitin sulfate (CS). Then, the component inhibiting the regeneration of axon in the above-mentioned nervous system disappear and therefore the regeneration of such an axon is promoted not only to construct a new neural network but also to achieve the recovery of neural functions. A number of examples like this have been reported (Non-patent Documents 4 to 6).
In addition, examples of diseases associated with nerve compression disorders in the above-mentioned nervous system include intervertebral disc hernia. The above-mentioned intervertebral disc hernia is a disease caused by bulging out of the nucleus pulposus in the intervertebral disc or the like, in which symptoms including lower back pain or the like develop because the bulged nucleus pulposus irritates the nerves around the nucleus pulposus.
As for a treatment of the above-mentioned intervertebral disc hernia, Japanese Patent Application Laid-Open Publication No.11-147837 (Patent Document 1) discloses a pharmaceutical composition for administration into spinal epidural space that contains a glycosaminoglycan-degrading enzyme and a pharmaceutical carrier. The above-mentioned glycosaminoglycan-degrading enzyme is an enzyme that degrades glycosaminoglycan into unsaturated oligosaccharides and unsaturated disaccharides and corresponds to a chondroitinase which degrades chondroitin sulfate (CS). Here, by administering the pharmaceutical composition containing the above-mentioned chondroitinase into spinal epidural space, the nucleus pulposus in the herniated intervertebral disc that migrates to such a spinal epidural space is efficiently digested and the phagocytosis of the nucleus pulposus by inflammatory cells is promoted. As a result, the above-mentioned Patent Document 1 describes that the invention thereof diminishes the nucleus pulposus migrated into the epidural space in an extremely efficient and effective fashion; and, on the top of that, there is an effect that the spinal cord is not affected at all.
In addition, there are examples where the above-mentioned chondroitinase is applied in a treatment of hypertrophic scar or keloid. For instance, WO 2009/072654 (Patent Document 2) discloses a promoter of elastic fiber formation that contains an enzyme degrading chondroitin sulfate A, chondroitin sulfate B, and chondroitin sulfate C. It is described therein that the administration of the above-mentioned promoter of elastic fiber formation to the area of the above-mentioned hypertrophic scar or keloid enables evaluation of the process of tissue normalization, which leads to reduction in the tissue volume of such a hypertrophic scar or keloid and complete cure of such a keloid or the like.
By way of example of enzymes degrading CS, there are chondroitinases such as ChABC, chondroitinase AC, chondroitinase ACII, chondroitinase ACIII, chondroitinase B, chondroitinase C, chondroitin sulfate ABC exolyase, and the like. In recent years, it has been known that hyaluronic acid-degrading enzymes of mammalian origin including Hyal-1 and PH-20 have an activity of degrading CS as well (Non-patent Documents 7 and 8).